Background: Newborn Respiratory Distress Syndrome (RDS) or what is known as surfactant deficiency disorder is a syndrome that affects premature infants who are born prematurely and is caused by a developmental deficiency in the production of pulmonary surfactant or as it is called immature formation of the lungs, or as a result of a defect in the protein gene that forms pulmonary surfactant. Non-invasive positive pressure ventilation (NIPPV) is the first technique for respiratory therapy while MISA and InSurE are both the most commonly used in RDS. Objective: To compare the use of the MISA method and the InSurE method in the treatment of premature infants less than 34 weeks of gestational age with respiratory distress syndrome (RDS). Patients and methods: The sample size was 70 infants with gestational age less than 34 weeks with RDS. 35 newborn were enrolled in each group. First group received surfactant via MIST technique and the other 35 newborn received it via InSurE technique. Infants in the InSurE group required intubation, according to previous collected data from the neonatal intensive care unit (NICU) center. Results: After the injection of surfactant, the 13 (37%) infants needed another dose in the MIST group, while only 3 (8.57%) infants in the InSurE group needed a second dose of the same substance. Accordingly, the response of the MIST group was shown to be a less improvement than the InSurE group in the child's breathing methods. Conclusion: The MIST method was the most successful with a rate of 96.5% in terms of time and the child's response to treatment, and the researcher recommended that the reasons for the effectiveness of MISA in treating RDS should be studied. However duration of invasive mechanical ventilation were higher in MIST group than InSurE group.